The role of AP-1 family transcription factor networks in regulating Th17 cell effector identity PROJECT SUMMARY CD4 T cells can adopt one of two opposing fates: that of a helper T cell (Th) specialized in supporting the clearance of infections, or that of a regulatory T cell (Treg) that functions to attenuate immune responses. Among the diversity of Th subset differentiation options, IL-17A-producing inflammatory Th17 cells stand out as unique by virtue of their relatively high level of inherent plasticity. While this feature can be advantageous during the clearance of an infection, it is less beneficial during inflammatory disease. Indeed, dysregulated Th17 cell function has been implicated in numerous autoimmune conditions. Moreover, Th17 cell plasticity exhibited in the context of inflammatory disease tends to take on Th1-like traits, such as expression of IFNg or T-bet, that are also associated with increased pathology. The underlying mechanisms that permit this plasticity are largely unknown. In this regard, we have recently identified several AP-1 family transcription factors (TFs) with opposing roles in promotion versus limitation of Th17 cell plasticity. Specifically, we have identified JunB as a factor that promotes Th17 cell identity by restraining alternative CD4 T cell programs during inflammation. In this supplement, we aim to determine the molecular mechanisms of JunB-regulated Th17 subset stabilization by investigating the dynamic changes in chromatin looping underlying Th17 cell plasticity, and testing the hypothesis that the central regulator of Th17 cell identity, JunB, facilitates such changes in chromatin organization. The development of chromatin conformation capture (3C) and its derivatives have yielded remarkable advances in understanding the role of the three-dimensional genome in gene regulation, however, how chromatin looping events are coordinated with, or mediated by, cell identity-regulating TFs such as JunB, is largely undefined. To this end, we will (i) initally define the global alterations in chromatin configuration that occur during Th17 cell effector conversion and their associated regulatory context; (ii) assess the requirement for JunB in regulating the formation of activating enhancer-promoter interactions at key effector loci defining CD4 lineage fate; and (iii) determine the global effects of JunB on the chromatin interactome during Th17 cell effector conversion. Together, the proposed work will utilize genetically modified mice and emerging global genomic interactome mapping approaches to study chromatin looping patterns during effector cell conversion and the cell intrinsic factors that modulate the chromatin interactome.